P1218: FIRST-IN-HUMAN STUDY OF CD19/BCMA DUAL-TARGETING FAST CAR-T GC012F FOR PATIENTS WITH RELAPSED/REFRACTORY B-CELL NON-HODGKIN’S LYMPHOMA
Authors: X. Chen, Y. Ping, L. Li, L. Zhang, X. Zhang, J. Huang, M. Sersch, Z. Wang, D. Song, H. Wang, L. Shen, W. Zhao, H. Zhang, M. Zhang, Y. Zhang
Journal: HemaSphere (2022)

Background: Relapse due to antigen escape remains a challenge for CD19-targeted chimeric antigen receptor T(CAR-T) cell therapy in B cell malignancies including B-cell non-Hodgkin's lymphoma (B-NHL). In addition, complete response (CR) rates of 40-54%, as reported in CD19-targeted CAR-T cell therapy for relapsed/refractory(r/r) large B-cell lymphoma, should be further improved. Aiming to optimize response rate and depth of response in B-NHL, a dual targeted CD19 and B cell maturation antigen (BCMA) CAR-T manufactured on the novel FasT CAR-T platform enabling 22-36 hours manufacturing was developed. Aims: We report early results of a phase 1 investigator initiated (IIT) dose escalation study of GC012F in r/r B-NHL (ChiCTR2100047061) to evaluate safety and preliminary efficacy. Methods: Patients (pts) with r/r B-NHL were eligible to be enrolled. Pts with active CNS involvement were excluded. The primary objectives were safety and tolerability, secondary objectives were pharmacokinetics and efficacy. Expansion of CAR-T cells was monitored by CAR copy number and flow cytometry. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASBMT, AE according to CTCAE 5.0. To date 3 Pts were enrolled and treated with a single dose of GC012F in escalating dosing cohorts after a standard LD regimen over 3 days (20-30 mg/m2 /day Flu, 250-300 mg/m2/day Cy). Results: Preclinical studies have shown that GC012F CAR-T cells specifically and effectively killed CD19+, BCMA+ and double positive tumor cell lines in vitro. In xenograft NOG mouse models, GC012F eliminated B cell lymphoma including DLBCL, MCL and Burkitt lymphoma cell lines. As of data cute-off February 22, 2022, with a median of 90 (range 29-92) days of follow-up, 3 pts with r/r DLBCL had received one GC012F infusion at dose levels 3.7*104 CAR- T/kg and 2-3*105 CAR- T/kg and completed at least 28 days of follow-up. Median age was 52 years (range 31-60). All pts presented with Ann Arbor stage IV disease. Two pts had IPI score 3, one had IPI score 2. One pt had dual expression of MYC and BCL2. Pts had received a median of 2 (range 2-3) prior lines of therapy. All pts presented with rapidly progressive disease especially pt 3 had a bulky nodal lesion with 12.2 cm in the long axis before lymphodepletion (8.6 cm at screening stage). No dose-limiting toxicities were observed. 2 pts experienced gr 1 CRS, 1 pt in DL 2 (3*105 CAR- T/kg) had gr 3 CRS over 2 days. No ICANS were observed. The median Tmax was 14d (range 14-14d), median peak copy number (Cmax) in peripheral blood was 89,120 (range 55,222-90,174) copies/mgDNA. CAR-T geometric mean AUC0-28 for pts was 753,873 (range 685,879-834,124) copies/mg DNA×day. All three pts achieved CR by PET-CT at day 28 after GC012F infusion, and response is ongoing at 3-months follow-up in the two assessable patients. Summary/Conclusion: The preliminary safety and tolerability of GC012F in r/r B-NHL at three different dose levels ranging from 3.7*104 CAR-T/kg-3*105 CAR-T/kg showed promising early and potent activity in r/r B-NHL pts with 100% CR rate at 1-month which was maintained in pts that were available to be assessed at the 3-month visit including r/r DLBCL pts and pts with bulky disease whose treatment is often challenging. Additional pts and longer follow up are needed to further evaluate these promising early results of GC012F in r/r B-NHL and to determine the RP2D for phase 2.